Nitric oxide releasing oxindole prodrugs for anagesic, anti-inflammatory and disease-modifying use

Abstract

Nitric oxide releasing oxindole prodrugs are described which are useful in methods of treating or preventing pain, inflammation, fever, or gastrointestinal lesions in a patient in need of such treatment, or of modifying an inflammatory disease or condition by favorably affecting the outcome thereof in said patient, wherein there is administered to said patient a therapeutically effective amount of a compound of Formula (I): and pharmaceutically acceptable salts thereof. In preferred embodiments, X is a covalent bond; R A and R B are both hydrogen; n is the integer 4; Y is —O—; Z is —NO 2 ; R C is a member selected from the group consisting essentially of 5-Cl and 5-F; R D is a member selected from the group consisting essentially of 6-Cl and 6-F; and R E is a member selected from the group consisting essentially of benzyl, 2-furyl, 2-thienyl, 5-chloro-2-thienyl and 5-trifluoromethyl-2-thienyl.

What is claimed is:  
     
         1 . A compound of Formula (I):  
                   
       and pharmaceutically acceptable salts thereof; wherein 
 X is a covalent bond, —O—, —S—, or —N(R 1 )— where R 1  is independently H or (C 1 -C 4 ) alkyl wherein said alkyl may be straight or branched chain;  
 R A  and R B  are members independently selected from the group consisting essentially of H; (C 1 -C 4 ) alkyl; (C 3 -C 6 ) cycloalkyl; phenyl; or taken together with the carbon atom to which they are attached, form a bridging (C 3 -C 6 ) cycloalkyl moiety; wherein said alkyl may be straight or branched chain, and wherein said alkyl, cycloalkyl, phenyl and bridging cycloalkyl moieties are independently substituted with 0 to 2 R 3 , where R 3  is a member selected from the group consisting essentially of F, Cl, Br, CF 3 , and (C 1 -C 4 ) alkoxy;  
 n is an integer selected from 1 through 6, inclusive;  
 Y is a covalent bond, —O—, —S—, or —N—;  
 Z is —NO or —NO 2 ;  
 R C  is a member independently selected from the group consisting essentially of H, F, Cl, Br, (C 1 -C 4 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylthio, CF 3 , (C 1 -C 4 ) alkylsulfinyl, (C 1 -C 4 ) alkylsulfonyl, NO 2 , phenyl, (C 2 -C 4 ) alkanoyl, benzoyl, thenoyl, (C 2 -C 4 ) alkanamido, benzamido, and N,N-di-(C 1 -C 3 ) alkylsulfamoyl;  
 R D  is a member independently selected from the group consisting essentially of H, F, Cl, Br, (C 1 -C 4 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylthio, and CF 3 ; or  
 R C  and R D  when taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group; or  
 R C  and R D  when taken together and when attached to adjacent carbon atoms, form a divalent radical D, wherein D is selected from the group consisting essentially of  
                 
 
 wherein W is O or S;  
 R E  is a member independently selected from the group consisting essentially of (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, phenyl, phenyl(C 1 -C 3 ) alkyl, phenoxy(C 1 -C 3 ) alkyl, thiophenoxy(C 1 -C 3 ) alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and —(CH 2 ) m —Q—R 2 ; wherein said phenyl, phenylalkyl and phenoxyalkyl moieties are independently substituted with 0 to 2 R 5 , where R 5  is a member selected from the group consisting essentially of F, Cl, Br, CF 3 , (C 1 -C 4 ) alkyl and (C 1 -C 4 ) alkoxy; m is 0, 1 or 2; Q is a divalent radical derived from a compound independently selected from the group consisting essentially of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]thiophene; and R 2  is a member selected from the group consisting essentially of H, F, Cl, Br, CF 3 , (C 1 -C 3 ) alkyl, and (C 1 -C 3 ) alkoxy; and  
 R 7  and R 9  are independently selected from the group consisting essentially of hydrogen, (C 1 -C 3 ) alkyl, —C(═O) (C 1 -C 3 ) alkyl, phenyl, and —C(═O)N(R 8 )(R 10 ), where R 8  and R 10  are independently selected from the group consisting essentially of hydrogen, (C 1 -C 3 ) alkyl, —C(═O) (C 1 -C 3 ) alkyl, and phenyl.  
 
     
     
         2 . A compound according to    claim 1    wherein X is a covalent bond, —O—, or —N(R 1 )—; R A  and R B  are independently selected from the group consisting essentially of hydrogen; methyl; ethyl; propyl; tert-butyl; cyclopropyl; cyclohexyl; phenyl; phenyl substituted by 1 or 2 R 3  where R 3  is F, Cl, CF 3 —, or CH 3 O—; and a bridging cyclopentyl moiety when taken together with the carbon atom to which they are attached; n is an integer selected from 3 through 6, inclusive; Y is —O— or —S—; and Z is —NO or —NO 2 .  
     
     
         3 . A compound according to    claim 2    wherein X is a covalent bond; R A  and R B  are independently selected from the group consisting essentially of hydrogen; propyl; tert-butyl; cyclopropyl; cyclohexyl; phenyl; phenyl substituted by 1 or 2 of F or CH 3 O—; n is an integer selected from 4 and 5; Y is —O—; and Z is —NO 2 .  
     
     
         4 . A compound according to    claim 3    wherein X is a covalent bond; R A  and R B  are both hydrogen; n is the integer 4; Y is —O—; and Z is —NO 2 .  
     
     
         5 . A compound according to    claim 3    wherein additionally R D  is hydrogen; R C  is a member selected from the group consisting essentially of 5-Cl, 6-Cl, 5-F, 6-F, 5-CF 3  and 6-CF  3 ; and R E  is a member selected from the group consisting essentially of benzyl substituted by 0 to 2 of R 5  where R 5  is F, Cl, or CF 3 ; and 2-furyl, 2-thienyl, (2-furyl)methyl, and (2-thienyl)methyl, each substituted by R 2  where R 2  is H, F, Cl, —CF 3 , —CH 3  or —OCH 3 .  
     
     
         6 . A compound according to    claim 5    wherein R C  is a member selected from the group consisting essentially of 5-Cl and 5-F; R D  is a member selected from the group consisting essentially of 6-Cl and 6-F; and R E  is a member selected from the group consisting essentially of benzyl, 2-furyl, 2-thienyl, 5-chloro-2-thienyl and 5-trifluoromethyl-2-thienyl.  
     
     
         7 . A compound according to    claim 4    wherein additionally R D  is hydrogen; R C  is a member selected from the group consisting essentially of 5-Cl, 6-Cl, 5-F, 6-F, 5-CF 3  and 6-CF  3 ; and R E  is a member selected from the group consisting essentially of benzyl substituted by 0 to 2 of R 5  where R 5  is F, Cl, or CF 3 ; and 2-furyl, 2-thienyl, (2-furyl)methyl, and (2-thienyl)methyl, each substituted by R 2  where R 2  is H, F, Cl, —CF 3 , —CH 3  or —OCH 3 .  
     
     
         8 . A compound according to    claim 7    wherein R C  is a member selected from the group consisting essentially of 5-Cl and 5-F; R D  is a member selected from the group consisting essentially of 6-Cl and 6-F; and R E  is a member selected from the group consisting essentially of benzyl, 2-furyl, 2-thienyl, 5-chloro-2-thienyl and 5-trifluoromethyl-2-thienyl.  
     
     
         9 . A compound according to    claim 6    wherein additionally R 7  and R 9  are both hydrogen; or they are both methyl; or one of R 7  and R 9  is hydrogen and the other is independently selected from the group consisting essentially of methyl; phenyl; and —C(═O)N(R 8 )(R 10 ), where R 8  and R 10  are both hydrogen, or they are both methyl, or one of R 8  and R 10  is hydrogen and the other is methyl.  
     
     
         10 . A compound according to    claim 8    wherein additionally R 7  and R 9  are both hydrogen; or they are both methyl; or one of R 7  and R 9  is hydrogen and the other is independently selected from the group consisting essentially of methyl; phenyl; and —C(═O)N(R 8 )(R 10 ), where R 8  and R 10  are both hydrogen, or they are both methyl, or one of R 8  and R 10  is hydrogen and the other is methyl.  
     
     
         11 . A compound according to    claim 1    wherein said compound is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         12 . A method of treating or preventing pain, inflammation, fever, or gastrointestinal lesions in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) as defined in    claim 1   .  
     
     
         13 . A method of treatment according to    claim 12    wherein said patient is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         14 . A method of treatment according to    claim 12    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3, 5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienyl methyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         15 . A non-enteropathogenic method of treating osteoarthritis, an inflammatory disease or condition, or a degenerative joint disease or condition in a patient in need of such treatment, comprising administering to said patient a therapeutically effective but non-enteropathogenic amount of a compound of Formula (I) as defined in    claim 1   .  
     
     
         16 . A method of treatment according to    claim 15    wherein said patient is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         17 . A method of treatment according to    claim 15    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         18 . A method of modifying an osteoarthritic, inflammatory, or degenerative joint disease or condition in a patient in need of such treatment, comprising administering to said patient an amount of a compound of Formula (I) which is therapeutically effective in halting or reversing the early stages of degeneration and decline in said patient's body tissues, organs, and basic functions associated with said disease or condition, whereby the outcome of said disease or condition is favorably affected.  
     
     
         19 . A method of treatment according to    claim 18    wherein said patient is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         20 . A method of treatment according to    claim 18    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato) propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         21 . A non-enteropathogenic method of treating and modifying an osteoarthritic inflammatory, or degenerative joint disease or condition in a pateint in need of such treatment, comprising administering to said patient a non-enteropathogenic amount of a compound of Formula (I) which is therapeutically effective in halting or reversing the early stages of degeneration and decline in said patient's body tissues, organs, and basic functions associated with said disease or condition, whereby the outcome of said disease or condition in said patient is favorably affected.  
     
     
         22 . A method of treatment according to    claim 21    wherein said patient is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         23 . A method of treatment according to    claim 21    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         24 . A pharmaceutical composition for treating or preventing pain, inflammation, fever, or gastrointestinal lesions in a patient in need of such treatment, comprising a pharmaceutically acceptable carrier and a compound of Formula (I) as defined in    claim 1   .  
     
     
         25 . A pharmaceutical composition according to    claim 24    wherein said patient being treated is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         26 . A pharmaceutical composition according to    claim 25    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         27 . A non-enteropathogenic pharmaceutical composition for treating osteoarthritis, an inflammatory disease or condition, or a degenerative joint disease or condition in a patient in need of such treatment, comprising a pharmaceutically acceptable carrier and a compound of Formula (I) as defined in    claim 1   .  
     
     
         28 . A pharmaceutical composition according to    claim 27    wherein said patient being treated is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         29 . A pharmaceutical composition according to    claim 28    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato] propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         30 . A pharmaceutical composition for modifying an osteoarthritic, inflammatory, or degenerative joint disease or condition in a patient in need of such treatment, comprising an amount of a compound of Formula (I) which is therapeutically effective in halting or reversing the early stages of degeneration and decline in said patient's body tissues, organs, and basic functions associated with said disease or condition, whereby the outcome of said disease or condition is favorably affected.  
     
     
         31 . A pharmaceutical composition according to    claim 30    wherein said patient being treated is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         32 . A pharmaceutical composition according to    claim 31    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato] pentyl ester.  
 
     
     
         33 . A non-enteropathogenic pharmaceutical compositions for use in modifying the course of an osteoarthritic, inflammatory, or degenerative joint disease or condition in a patient in need of such treatment, comprising a non-enteropathogenic amount of a compound of Formula (I) which is therapeutically effective in halting or reversing the early stages of degeneration and decline in said patient's body tissues, organs, and basic functions associated with said disease or condition, together with a pharmaceutically acceptable carrier for said compound of Formula (I).  
     
     
         34 . A pharmaceutical composition according to    claim 33    wherein said patient being treated is a mammal comprising a livestock animal, a companion animal, or a human.  
     
     
         35 . A pharmaceutical composition according to    claim 34    wherein said compound of Formula (I) as defined in    claim 1    is a member selected from the group consisting essentially of: 
 5-Nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester, (E) and (Z) separate isomers;  
 5-S-nitroso-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 3-S-nitroso-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 2-(3,5-Difluorophenyl)-3-nitrato-propylcarbamic acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 4-(3,5-Dimethoxyphenyl)-5-nitrato-valeric acid-[6-chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)] ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[4-(nitrato)] butyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 1-(2-cyclopropyl-3-nitrato)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 1-[3-(1-tert-butyl-2-nitrato)ethyl]cyclopentyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid (4-cyclohexyl-4-nitrato-2-propyl)propyl ester;  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]-S-thioformic acid 2-[ (2-methoxy)phenyl-3-nitrato]propyl ester; and  
 [6-Chloro-5-fluoro-2-oxindole-1-carboxamide-3-(2-thienylmethyl)oxy]formic acid 2-[(3,6-difluorophenyl)-5-nitrato]pentyl ester.  
 
     
     
         36 . A pharmaceutical composition comprising a compound of Formula (I) as defined in    claim 1    in combination with one or more other therapeutically active agents under the following conditions: 
 A. where a joint has become seriously inflammed as well as infected at the same time by bacteria, fungi, protozoa, and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal, and/or antiviral therapeutic agents; or  
 B. where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of: 
 1. NSAIDs;  
 2. H 1 -receptor antagonists;  
 3. kinin-B 1 - and B 2 -receptor antagonists;  
 4. prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PGI 2 -, and PGE-receptor antagonists;  
 5. thromboxane A 2  (TXA2-) inhibitors;  
 6. 5- and 12-lipoxygenase inhibitors;  
 7. leukotriene LTC 4 -, LTD 4 /LTE 4 -, and LTB 4 -inhibitors;  
 8. PAF-receptor antagonists;  
 9. gold in the form of an aurothio group together with one or more hydrophilic groups;  
 10. immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate;  
 11. anti-inflammatory glucocorticoids;  
 12. penicillamine;  
 13. hydroxychloroquine;  
 14. anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone, and benzbromarone.